ELF4 is a critical component of a miRNA-transcription factor network and is a bridge regulator of glioblastoma receptor signaling and lipid dynamics

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Kosti, Adam ; Chiou, Jennifer ; Guardia, Gabriela D. A. ; Lei, Xiufen ; Balinda, Henriette ; Landry, Tesha ; Lu, Xiyuan ; Qiao, Mei ; Gilbert, Andrea ; Brenner, Andrew ; Galante, Pedro A. F. ; Tiziani, Stefano ; Penalva, Luiz O. F.

• Tipo de documento: Artigo Científico
• Fonte: NEURO-ONCOLOGY; v. N/A, p. 12-pg., 2022-07-21.

Resumo

Background The loss of neurogenic tumor suppressor microRNAs miR-124, miR-128, and miR-137 is associated with glioblastoma's undifferentiated state. Most of their impact comes via the repression of a network of oncogenic transcription factors. We conducted a high-throughput functional siRNA screen in glioblastoma cells and identify E74 like ETS transcription factor 4 (ELF4) as the leading contributor to oncogenic phenotypes. Methods In vitro and in vivo assays were used to assess ELF4 impact on cancer phenotypes. We characterized ELF4's mechanism of action via genomic and lipidomic analyses. A MAPK reporter assay verified ELF4's impact on MAPK signaling, and qRT-PCR and western blotting were used to corroborate ELF4 regulatory role on most relevant target genes. Results ELF4 knockdown resulted in significant proliferation delay and apoptosis in GBM cells and long-term growth delay and morphological changes in glioma stem cells (GSCs). Transcriptomic analyses revealed that ELF4 controls two interlinked pathways: 1) Receptor tyrosine kinase signaling and 2) Lipid dynamics. ELF4 modulation directly affected receptor tyrosine kinase (RTK) signaling, as mitogen-activated protein kinase (MAPK) activity was dependent upon ELF4 levels. Furthermore, shotgun lipidomics revealed that ELF4 depletion disrupted several phospholipid classes, highlighting ELF4's importance in lipid homeostasis. Conclusions We found that ELF4 is critical for the GBM cell identity by controlling genes of two dependent pathways: RTK signaling (SRC, PTK2B, and TNK2) and lipid dynamics (LRP1, APOE, ABCA7, PLA2G6, and PITPNM2). Our data suggest that targeting these two pathways simultaneously may be therapeutically beneficial to GBM patients. (AU)

• Processo FAPESP: 17/19541-2 - Impacto de proteínas de ligação a RNA na desregulação de splicing em glioblastoma
• Beneficiário: Gabriela Der Agopian Guardia
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 18/15579-8 - Retroelementos: uma força motriz criando novidades genéticas no genoma humano e de camundongos
• Beneficiário: Pedro Alexandre Favoretto Galante
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores - Fase 2